2-({62 -Aminoacryloyl)iminobenzothiazolines

ABSTRACT

7H-Thiazolo(3,2-a)pyrimidin-7-ones, Beta aminoacryloyliminothiazoline derivatives thereof and their benzothiazole and benzothiazoline analogues possess anti-fungal, amoebicidal and anti-inflammatory activity, and may be prepared by reaction of a 2-aminothiazole or 2-aminobenzothiazole with a propiolic acid or ester thereof followed optionally by reaction with an amino, or with propiolyl chloride followed by reaction with an amine.

United States Patent [191 Evans 2-(B-AMINOACRYLOYL)IMINOBENZO-THIAZOLINES [75] lnvcntor: Delme Evans, Chalfont St. Peter [El] Appl.No: 4l0,869

Related US. Application Data [62] Division of Ser. No. 182.122. Sept,20. l97l. Pat

{30] Foreign Application Priority Data Sept 30, I970 United Kingdom46404/70 [52] US. Cl 260/240 J; 260/305 [5 [1 Int. Cl. C071) 277/82 [58]Field of Search 260/251 A, 305, 293, 57

[56] References Cited UNlTED STATES PATENTS 2.691099 12/1954 Knott .e260/305 Nov. 11, 1975 3.53UJ42 9/l97t) Nair cl alum. 260/305 3.538.086ll/ I970 Mair ct ill, 360/25] A 3.8l3.36() 5/1974 Ennis i l 260/251 AFORElGN PATENTS OR APPLICATIONS 6031123 |()/|'-)34 German) a a V r HZfiU/ZSI A OTHER PUBLlCATlONS Matsunaga et al. Index Uiemicus Abstractof Yakugaku Zasshi 88(8), IOOfT-IOlO [968).

Primary lixamim'rRichard J Gallagher Attorney, Agent, or Firm-William B.Scanlon: Evcret F. Smith [57] ABSTRACT 7H-Thiaz0lo[ 32alpyrimidinJ-ones. Bamin0acryloyliminothiuzoline derivatives thereof andtheir benzothiazole and hcnzothiazoline analogues possess anti-fungal,amoebicidal and anti-inflammatory activity, and may be prepared byreaction of a 2- aminothiazole or Z-aminobenzothiuzole with a propiolicacid or ester thereof followed optionally by reaction with an amino orwith propiolyl chloride followed by reaction with an amine 7 Claims, N0Drawings Z-(B-AMINOACRYLOYL)!MINOBENZOTHIAZO- LINES This is a divisionof application Ser. No. 182,122 filed Sept. 20, 1971 now US. Pat. No.3,813,360.

This invention relates to new chemical compounds having a heterocyclicring structure and provides methods by which such compounds may beprepared. The compounds of the invention are useful as anti-fungal,amoebicidal and/or anti-inflammatory agents and the invention thereforealso provides compositions comprising said compounds in association witha suitable carrier or diluent therefor According to the presentinvention therefore, there are provided compounds of the formula:

wherein either (a) R" and R together represent the chain or (b) R ishydrogen and R represents the group =N CO-CH=CHNRR"; R, R and R, whichmay be the same or different, represent hydrogen, C alkyl, C alkoxy, Ccarbalkoxy or phenyl, or R is as defined abovoe and R and R togetherrepresent a phenyl ring optionally substituted by one or two C alkyl, Calkoxy, or C carbalkoxy; and R and R" separately represent hydrogen or Calkyl or together with the adjacent nitrogen represent pyrrolidino,piperidino or homopiperidino.

The term C alkyl" as used herein means straight and branched hydrocarbonchains having up to 6 carbon atoms such as methyl, ethyl, n.propyl,isopropyl, n.butyl, isobutyl, s.butyl, t.butyl, n.pentyl, s.pentyl,n.hexyl, 3-methylpentyl, 2-ethylbutyl, and 1,l-dimethylbutyl. The termsC alkoxy and C carbalkoxy" as used herein mean the aforementioned Calkyl groups linked to the heterocyclic nucleus through an O- or-O.CO-group respectively. Preferred alkyl substituents for use in thepresent invention are those mentioned above having up to 4 carbons.Preferred alkoxy substituents also contain up to 4 carbons such asmethoxy, ethoxy, isopropoxy, n-butoxy, s.butoxy, and t.butoxy whilstpreferred carbalkoxy substituents are carbomethoxy and carboethoxy.Exemplary of compounds of formula 1(a) i.e. compounds of the structure:

which are of the use in accordance with the invention are:

7H-thiazolo[ 3 ,2-a]pyrimidin-7-one2,3-diethyl-7H-thiazolo[3,2-alpyrimidin-7-one 3-methyL7H -thiazolo[3,2-a1pyrimidin-7 -one3-methyl-5-n.butyl-7H-thiazolo[3,2-a]pyrimidin-7one 23-n.hexyl-S-methyl-7H-thiazolo[3,2-a]pyrimidin-7-one3,S-dimethoxy-7H-thiazolo[3,2-a]pyrimidin-7-one3,5-dimethyl-7H-thiazolol 3,2-a lpyrimidin-7-one3-isobutoxy-5-phenyl-7H-thiaz0lo[ 3 ,2-a ]pyrimidin- 7-one3-carboethoxy-5-phenyl-7H-thiazolo[ 3,2-a]pyrimidin- 7-one 3-methyl-5-phenyl-7H-thiazolo[ 3,2-a]pyrimidin-7-one2,3-dimethoxy-S-carbomethoxy-7l-l-thiazolo[ 3 ,2-

a]pyrimidin-7-one 3-methyl-5-carbomethoxy-7H-thiazolo[ 3,2-alpyrimidin-7-one 3-phenyl-7H-thiazolol 3 ,2-a] pyrimidin-7-one3-phenyl-5-n.propyl-7H-thiazolo[3,2-a]pyrimidin- 7-one 2H-pyn'midino[ 2,l -b]benzothiazol-2-one 6,8-di-t.butyl-2H-pyrimidino[ 2,l-b]benzothiazol- 2-one 4,6-diethyl-2H-pyrimidino[ 2, l-b]benzothiazol-2-one 4-carbomethoxy-7,9-dimethoxy-2l-l-pyrimidin0[ 2,1

blbenzothiazol-2-one 8-methyl- 2H-pyrimidino[ 2, l -b]benzothiazol-2-one 4,6,8-trimethyl-2H-pyrimidino[ 2, l-blbenzothiazol-2-one 4-carboethoxy-2H-pyrimidino[ 2 l -b benzothiazol- 2-one4-methyl-8-methoxy-2H-pyrimidino[ 2, l -b]benzothiazol- 2-one7,9-diethoxy-2H-pyrimidino[2, l -b]benzothiazol-2-one whilst examples ofuseful compounds of l(b) i.e. compounds of the structures:

are

2-( B-ethylaminoacryloyl )imino-A"-thia1oline 2-( B-nbutylaminoacryl oyl)imino- N-thiazoline 2-( B-N,N-dimethylaminoacryloyl )imino- -thiazoline2-( B-ethylaminoacryloyl )imino-4-methyl- N-thiazoline 2-( fiethylaminoacryloyl )imino-4,5-diethyl-A"-thiazoline 2-(,B-Lbutylaminoacrylo yl )imino-4-phenyl-A -thiazo' line 2-(fl-pyrrolidinoacryloyl )imino- A -thiazoline 2-( B-pipe ridinoacryloyl)imino-N-thiazoline 2-( fi-homopiperidinoac ryloyl )imino-4-methoxy- A"-thiazoline 2-( B-ethylaminoacryloy l )iminobenzothiazoline 2-(B-N,N-dipropylamin oacryloyl )iminobenzothiazoline 2-(B-nbutylaminoacryloyl )imino-S ,6-dimethoxybenzothiazoline 2-(B-nbutylaminoacryloyl )imino-Sethylbenzothiazoline 2-(B-pyrrolidinoacryloyl )iminobenzothiazoline 2-( B-pipe ridinoacryloyl)iminobenzothiazoline 2-( B-nbutylaminoacryloyl)imino-6-methylbenzothiazoline Y 2-( B-n. butylaminoacryl oyl)imino-6methoxybenzothiazoline According to a feature of the presentinvention, there is provided a process for preparing the compounds offormula 1 comprising condensing an appropriate 2- aminothiazole orZ-aminobenzothiazole of the formula:

wherein R and R are as defined in formula 1, with a suitable propiolicacid or ester thereof of the formula:

R-() C-COOR m wherein R is as defined above and R is hydrogen or Cpreferably C alkyl to produce a compound of formula l(a), andthereafter, when a compound of formula [(b) is desired, reacting acompound of formula 1(a) in which R is hydrogen with an amine of theformula HNRR".

The condensation of compounds of formulae II and III is normally carriedout in a suitable reaction solvent such as an alkanol and particularlyethanol. The reaction may be carried out at room temperature but reducedreaction times may be obtained at higher temperatures, conveniently atthe reflux temperature of the reaction mixture. Improved yields may beobtained by carrying out the condensation in the presence of a basiccatalyst such as a quaternary ammonium hydroxide or alkoxide,particularly tetramethyl ammonium hydroxide, methoxide or ethoxide.

In the reaction of a compound of formula l(a) in which R is hydrogenwith an amine of the formula HNR R cleavage of the thiazolopyrimidinoneor pyrimidinobenzothiazolone nucleus occurs at the 5- or 4- positionsrespectively to form the desired compound of formula [(b). The reactionmay be carried out in the presence or absence of a suitable solvent,such as water or ethanol, depending on the amine being used.Advantageously, the reaction medium contains a small amount of asuitable base, for example a quatemary ammonium hydroxide such astetramethyl ammonium hydroxide, and preferably the reaction is carriedout at the reflux temperature of the reaction medium.

The compounds of formula [(b) may alternatively be prepared inaccordance with a further feature of the present invention by reactionof a compound of formula ll with propiolyl chloride to produce aninterme diate compound of the formula:

R NHCOCECH which on reaction with the amine HNRR yields the desiredcompound of formula l(b). The first stage in this reaction is normallycarried out at low temperatures of from to +20C. by adding the propiolylchloride slowly with agitation to the Z-aminothiazole. The resultantcompound of formula IV, before or after purification, may then be addedto the required amine and the reaction allowed to proceed at lowtemperatures such as those used in the first stage.

Compounds of formula [(a) and l(b) possess useful anti-inflammatoryactivity and amoehicidal activity respectively at doses between 50 and300 mgJKg. These compounds also possess a low oral toxicity which interms of LD in mice ranges from about 200 mg./Kg. to l600mg./Kg.

According to a feature of the present invention therefore, there isprovided a method of treating inflammation or amoebiasis in animals.including humans, which comprises administering to said animal aneffective dose of a compound of formula I possessing antiinflammatory oramoebicidal activity. The effective dose for animals other than humanswill normally be within the above-mentioned dosage range, whilst forhumans the dose will normally be between 10 and mg./Kg, repeated untilthe condition is relieved. It will, of course, be appreciated that thehuman dosage regime will be determined by a physician in the light ofall the relevant circumstances including the condition to be treated,the physical condition of the patient, the choice of compound to beadministered and the route of administration and therefore the abovedosage range is not intended to limit the scope of the invention in anyway.

The compounds of formula I will normally be administered in compositionform and accordingly the present invention also provides pharmaceuticalcompositions comrpising at least one compound of formula In inassociation with a pharmaceutically acceptable carrier therefor.

The compositions of the present invention may be administered orally,parenterally or rectally in the form of, for example, tablets, capsules,suppositories or suspensions. Advantageously for this purpose,compositions may be provided in dosage unit form, preferably each dosageunit containing from 50 to 1000 :ng., more advantageously 250 to 750mg., of a compound of formula I.

In this Specification the expression dosage unit form is used as meaninga physically discrete unit containing an individual quantity of theactive ingredient, generally in admixture with a pharmaceutical diluenttherefor or otherwise in association with a pharmaceutical carrier, thequantity of the active ingredient being such that one or more units arenormally required for a single therapeutic administration or that, inthe case of severable units such as scored tablets, at least onefraction such as a half or quarter of a severable unit is required for asingle therapeutic administration,

The formulations of the present invention normally will consist of atleast one compound of formula I mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by a carrier in the form of acapsule, sachet, cachet, paper or other container. A carrier or diluentmay be a solid, semi-solid or liquid material which serves as a vehicle,excipient or medium for the active therapeutic substance. Some examplesof the diluents or carriers which may be employed in the pharmaceuticalformulations of the present invention are lactose, dextrose, sucrose,sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquidparaffin, cocoa butter, oil of theobroma, alginates, tragacanth,gelatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitanmonolaurate, and methyland propyl-hydroxybenzoate. In the case oftablets, a lubricant may be incorporated to prevent sticking and bindingof the powdered ingredients in the dies and on the punch of thetabletting machinev For such purpose, there may be employed for instancetalc; aluminium, magnesium or calcium stearate; or mineral oil.

Certain of the compounds of formula I also possess anti-fungal activityuseful for the control of plant pathogens, particularly Barr -[iscinerea, the causative organism of grey mould on grapes.

The fungicidally active compounds of formula I can be employed for theprotection of plants susceptible to pathogenic fungi and thereby preventthe onset of disease symptoms. They can likewise be used in thetreatment of infected plants. When so used, the active compounds can beformulated as a solution, emulsion or emulsifyable concentrate, or as adust. They are preferably formulated as a solution suitable for foliarspray application. Aqueous solutions of the active compounds atconcentrations of from about 500 to about 4000 ppm. can be prepared withthe aid of a solubilizing agent and are useful fungicidal spraysolutions when applied to the foliage of susceptible plants. Likewise,aqueous emulsions of the compounds of the invention can be prepared insimilar concentrations with the aid of an emulsifier and a solubilizingagent. The aqueous solutions and emulsions desirably contain a wettingagent to enhance the spreadability of the fonnulations over the leafsurface. Suitable emulsifying agents can be of the ionic or non-ionictypes, such as the condensation products of alkylene oxides with phenolsand organic acids, polyoxyethylene derivatives of sorbitan esters,aralkyl and alkyl sulfonates and the like.

Concentrated dust formulations can be prepared by incorporating fromabout to about 45 per cent of a fungicidally active compound of formulaI in a finely divided inert solid carrier, such as diatomaceous earth,fullers earth, bentonite, talc, and the like. Such dust formulations canbe used directly or they can be further diluted with inert carrier toachieve lower concentrations of the active compound. Alternativelydispersing and/or wetting agents may be incorporated to form wettablepowder concentrates which subsequently may be dispersed in water orother aqueous carriers to form spray compositions.

The compounds of formula l(b) are also active against fungi causingderrnatomycoses in human and animals, such as Trychophytonmentagrophyres. In use in the treatment of derrnatomycoses, thecompounds of formula l(b) may be formulated as solid, semi-solid' orliquid compositions containing, in addition to theactive ingredient,suitable pharmaceutically acceptable adjuvants such as wetting agents,dispersing agents, and solubilising agents. Exemplary of suchcompositions are creams, ointments, dusting powders, tinctures,antiseptic soaps and shampoos, all of which are prepared in a well knownmanner and preferably contain from 0.5 to 10% of the active ingredient.V

The following Examples will further illustrate the preparation of thecompounds of this invention:

EXAMPLE 1 Ethyl propiolate (1.0 g.) was added'to a warm solution of2-aminothiazole (10.0 g.) in ethanol (100 ml.). The solution was heatedunder reflux for 8 hours during which time a solid was precipitated. Thereaction mixture was cooled, filtered and the solid obtainedre-crystallised from dimethylformamide to yield 7H-thiazolo[3,2-a]pyrimidin-7-one, m.p. 263266C. (dec.). Yield 7.7 g., 51%.

The reaction was repeated but the refluxing was carried out in thepresence of a trace (3 drops) of a 25% aqueous solution oftetramethylammonium hydroxide. The desired product was obtained in ayield of 9.7 g., 64%.

EXAMPLE2 By the method of Example 1, 3-methyl-7H-thiazolo[3,2-a1pyrimidin-7-one, m.p. 284287C.

(dec.), yield 62%, was prepared from methyl propiolate and2-amino-4-methylthiazole.

EXAMPLE 3 By the method of Example 1, 3,5-dimethyl-7H-thiazolo[3,2-a1pyrimidin-7-one, m.p. 265-268C. (dec. yield 61%, wasprepared from fi-methyl propiolic acid and 2-amino-4-methylthiazole.

EXAMPLE 4 By the method of Example I, 3-methyl-5-phenyl-7H-thiazolo[3,2-a]-pyrimidin-2-one, m.p. 270272C. (dec.), yield 47%, wasprepared from ethyl B-phenylpropiolate and 2-amino-4-methylthiazole.

EXAMPLE 5 By the method of Example 1,3-methyl-5-carbomethoxy-7H-thiazolo-[ 3,2-a]pyrimidin-7-one, m.p.l45-l47C. (dec.), yield 24%, was prepared from acetylene dicarboxylicacid dimethyl ester and 2- amino-4- methylthiazole EXAMPLE 6 By themethod of Example I, 3-phenyl-7H- thiazole[3,2-alpyrimiclin-7-one, m.p.236-238C.

(dec.), yield 29%, was prepared from ethyl propiolate and2-amino-4-phenylthiazole.

EXAMPLE 7 By the method of Example I,2H-pyrimidino[2,lblbenzothiazole-Z-one, m.p. 272275C. (dec.), yield 69%,was prepared from ethyl propiolate and 2- aminobenzothiazole.

EXAMPLE 8 By the method of Example 1, 8-methyl-2H- pyrimidino[ 2,l-b]-benzothiazole- 2-one, m.p. 295-297C. (dec.), yield 56%, wasprepared from 2- amino-6-methylbenzothiazole and ethyl propiolate.

EXAMPLE 9 By the method of Example 1, 4-methyl-8-methoxy-2H-pyrimidino-[ 2, l -b] benzothiazole-Z-one m .p. 267270C. (dec.),yield 34%, was prepared from 2- amino-6-methoxybenzothiazole and ethylfl-methylpropiolate.

EXAMPLE 10 By the method of Example 1, 8-methoxy-2H-pyrimidino[2,l-b]benzothiazole-2-one, m.p. 300C., was prepared from2'amino-6-methoxybenzothiazole and ethyl propiolate.

EXAMPLE 1 I [3,2-a]pyrimidin-7-one, m.p.

[3,2-a1pyrimidin-7-one, mp.

{2, l -b]benzothiazole-2-one,

7 6-methoxy-2H-pyrimidino [2, l -b]benzothiazole-2-one.

m.p. 2456 C. (dec.)

EXAMPLE l2 A mixture of 7-H-thiazolo[3,2-a]pyrimidin-7-one 1.5g), 70%aqueous ethylamine solution (50 ml.) and a 25% aqueous solution oftetramethyl ammonium hydroxide drops) was heated under reflux for 7hours, the solid dissolving slowly during this time. Evaporation of thewater under reduced pressure and recrystallisation of the residue fromethanol yielded crystals of 2- (B-ethylaminoacryloyl)imino-N-thiazeline 1. 1 5g., 59%), mp. 208210C. (dec.).

EXAMPLE l3 Using the method of Example l2, the following compounds wereprepared from the appropriate starting materials:

2-( B-n Butylaminoaryloyl imino-N-thiazoline, m.p.

l52-154C., in 52% yield.

2-( B-Piperidinoacryloyl )imino- A -thiazoline, m.p.

201203C. in 72% yield.

Z-(B-Ethylaminoacryloyl)iminobenzothiazoline. m.p.

l75-178C., in 72% yield. 2-( B-nButylaminoacryloyl)iminobenzothiazoline, m.p.

202204C., in 25% yield.

2-( B-Pyrrolidinoacryloyl )iminobenzothiazoline, m.p.

2152l7C. (dec.), in 68% yield.2-(fi-Piperidinoacryloyl)iminobenzothiazoline. m.p.

2l9-22lC (dec.), in 65% yield.

2-( fi-nButylaminoacryloyl )imino-6-methylbenzothiazoline. m.p. l203C.

2-( B-n. Butylaminoacryloyl )imino-6-methoxybenzothiazoline, m.p.l76l78C.

EXAMPLE 14 A solution of propiolyl chloride (4.43 g.) in toluene (20ml.) was added dropwise to a stirred solution of 2- aminothiazole (5.0g.) in ether (200 ml.) kept at l0C. When the addition was complete (30minutes), the mixture was stirred at room temperature for a further 30minutes and then filtered. The resultant solid was washed with ether anddried over phosphorus pentoxide. The solid (100 mg.) was added topiperidine (2 ml.) at 0C. and the solution stood at room temperatureovernight. The piperidine was removed at room temperature under reducedpressure and the residue recrystallized from ethanol to yield 2-(B-piperidinoacryloyl)imino-N-thiazoline, which was identical with thematerial produced by the alternative synthetic route described inexample 12.

For the avoidance of doubt, the numbering used in the naming of theforegoing compounds is as follows:

Thiazolopyrimidinones Pyrimidinobenzothiazoloncs 2- B-aminoacryl oyl)imino- N-thiazolines 2-( B-aminoacrylo yl )iminobenzothiazolines whereR and R represent the optional substituents on the phenyl ring.

I claim:

1. The compound of the formula N-CO-CH CR-NR R R and R independently areselected from the group consisting of hydrogen, C,C alkyl, C,C alkoxyand C C-, carbalkoxy,

and R and R taken separately are hydrogen or C -C alkyl, and takentogether with the adjacent nitrogen are pyrrolidino, piperidino orhomopiperidino.

2. The compound of claim 1, wherein R and R are taken separately and Ris hydrogen and R is ethyl or n-butyl or R and R together with theadjacent nitrogen represent piperidino.

3. The compound of claim 2 said compound beingZ-(B-ethylaminoacryloyl)iminobenzothiazoline.

4. The compound of claim 2 said compound being 2-(B-n-butylaminoacryloyl )iminoboen zothiazoline.

5. The compound of claim 2 said compound being2-(B-n-butylaminoacryloyl)imino-b-methylbenzd thiazoline.

6. The compound of claim 2 said compound being 2-( fim-butylaminoacryloyl )imino--methoxybenzothiazoline.

7. The compound of claim 2 said compound being 2-( B-piperidinoacryloyl)iminobenzothiazoline.

1. THE COMPOUND OF THE FORMULA
 2. The compound of claim 1, wherein R7and R8 are taken separately and R7 is hydrogen and R8 is ethyl orn-butyl or R7 and R8 together with the adjacent nitrogen representpiperidino.
 3. The compound of claim 2 said compound being 2-( Beta-ethylaminoacryloyl)iminobenzothiazoline.
 4. The compound of claim 2said compound being 2-( Beta-n-butylaminoacryloyl)iminoboenzothiazoline.
 5. The compound of claim 2said compound being 2-( Beta-n-butylaminoacryloyl)imino-6-methylbenzothiazoline.
 6. The compound ofclaim 2 said compound being 2-( Beta-n-butylaminoacryloyl)imino-6-methoxybenzothiazoline.
 7. The compound ofclaim 2 said compound being 2-( Beta-piperidinoacryloyl)iminobenzothiazoline.